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Menstrual cycle-related sensitivity to 35% CO2 in panic patients
Menstrual Cycle-Related Sensitivity to 35 % C O 2 in Panic Patients Giampaolo Perna, Francesca Brambilla, Cinzia Arancio, and Laura Bellodi
In a double blind, random, cross-over design, 10 patients and seven controls inhaled one vital capacity of 35% C02-65% Oz during their early-follicular and midluteal phases. Anxiety after CO: intake was significantly stronger in the early-follicular phase than in the midluteal phase for patients. Controls had no anxie~, reactions. Key Words: Sex hormones, panic, CO2
Introduction Clinical evidence and data from controlled studies suggest that sex hormones might modulate the clinical expression of panic disorder (PD) (Klein 1993). Clinical observations and data from retrospective studies (Breier et al 1986; Sandberg et al 1986) suggest that PD is exacerbated in the premenstrual period, perhaps related to the rapid fall of blood progesterone (Klein 1993), whereas data from prospective studies are inconsistent. Cameron et al (1988) found a premenstrual exacerbation of the severity of panic attacks, while Stein et al (1989) and Cook et al (1990) did not find any significant relationship between menstrual cycle and severity or frequency of panic. It has been suggested that pregnancy influences the clinical expression of PD. Two early retrospective studies by Cohen and White (1951 ) and Wheeler et al (1950) reported an exacerbation of panic symptomatology, while a case
From the Anxiety Disorders Clinical and Research Unit. Department of Neuropsy chiatric Sciences, University of Milan San Raffaele Hospital (GP, CA. LB), and Centro di Psiconeuroendocrinologia, Psychiatric Hospital Paolo Pini (FB), Milan, Italy. Address reprint requests to Prof. L. Bellodi, Dept. of Neuropsychiatric Sciences, University of Milan, San Raffaele Hospital. 29 via Prinetti, 20127, Milan, Italy. Received January 31.1994; revised May 1994.
© 1995 Society of Biological Psychiatry
study by George et al (1987) and retrospective studies by Klein (1964), Cowley and Roy-Byrne (1989), and Villeponteaux et al (1992) reported improvement of PD during pregnancy. Finally, a case study by Verburg et al (in press) reported improvement of PD in the first half of pregnancy and a recurrence of panic symptoms in the second half. Panic symptomatology has been reported to worsen postpartum (Metz et al 1988, 1989), with lactation apparently being protective (Klein 1993; Cowley and Roy-Byrne 1989). Oral contraceptives (Deci et al 1992; Ushiroyama et al 1992) and estrogen replacement treatment (Price et al 1988) have been reported to provoke panic attacks. Finally, late luteal phase dysphoric disorder has shown rates of provoked panic-like attacks similar to those in PD (Harrison et al 1989; Facchinetti et al 1992; Sandberg et a11993). Hypersensitivity to CO2 (Gorman et al 1989), in the context of the "False Suffocation Alarms" theory developed by Klein (1993), and abnormal noradrenergic function (Charney et al 1986; Brambilla et al, in press) may be etiopathogenetic factors in PD. Both fluctuate during the menstrual cycle, possibly influenced by progesterone (England and Farhi 1976; Dutton et al 1989) and estrogen levels (Blum et al 1992). We have investigated the changes in anxiety provoked in PD patients by inhalation of one vital capacity of 35% CO2 (Griez et al 1987; Perna et al 1994) during the early follicular and midluteal phases. 0006-3223/95/$09.50 SSDI 0006-3223(94)00154-U
Menstrual Cycle-Related Sensitivity to CO2 in Panic Patients
T a b l e 1. D e m o g r a p h i c C h a r a c t e r i s t i c s o f S a m p l e
Age (years) Menstrual cycle length (days) Age at onset (years) No. of panic attacks during last month Agoraphobia
Panic patients (n = 10)
Controls (n = 7)
32.t + 6.6 27.1 ~+ 1.8 29.1 ~ 6.7
25.9 --+ 5.4 28,6 + 1.8
5.6 _+ 4.4 8
All values, except for agoraphobia, are expressed as mean + SD.
Methods Subjects The subjects were 10 physically healthy women with PD, consecutively recruited over I year at the Anxiety Disorders Clinical and Research Unit, San Raffaele Hospital, Milan, and seven healthy women without any lifetime Axis I disorders and with no personal histories of panic attacks. Diagnoses were made according to the Diagnostic Interview Schedule, Revised (DIS-R) (Robins et al 1989), and the data collected were analyzed by computer software (Marcus et al 1990). None of the subjects participating to the study met DSM-III-R (APA 1987) criteria for Late Luteal Phase Dysphoric Disorder. Table 1 lists the demographic and clinical characteristics of the sample. Criteria for exclusion were: current or recent (past 6 months) pregnancy, lactation, or abortion; irregular menstrual cycle; endocrinopathies; use of oral contraceptives; chronic use of any medication, and, for patients, any lifetime psychiatric diagnoses other than PD according to DSM-III-R (APA 1987). Participants gave their informed consent and were requested to avoid medications affecting sex hormone or prolactin (PRL) levels and any psychotropic drug for at least 2 weeks, alcohol for at least 36 hours, xanthines, smoking, and food for at least 8 hours before testing.
Procedure The investigators who performed the challenges were blind to the menstrual phase and the diagnosis of the participants. Participants in the study were blind to the order of administration of gas mixtures. According to period of admission to the study, the first day of the challenge in 5 patients and 3 controls coincided with the midluteal phase, and in 5 patients and 4 controls with the early follicular phase. Order of gas administration was not randomized, since previous studies showed no significant effect of order on reactivity to 35% CO2 (Gorman et al 1990; Perna et al, 1994). 35% CO2 challenges were given in the very early follicular phase (day 4 of the cycle), in which pituitary and ovarian hormone levels are still minimal, and in the midluteal phase, (day -8
B1OL PSYCHIATRY ! 995:37:528-532
529
before menses) in which most of the hormonal levels are maximal. Days 4 and - 8 were based on regular menstrual cycles. On the first day of the challenge, at 8:00 AM blood was drawn and treated with ethylenediamine tetraacetic acid (EDTA), and assays were drawn for progesterone (PRG), estrogen (ESTR), follicle-stimulating hormone (FSH), and luteotrophic hormone (LH), prolactin (PRL). Plasma was frozen at -20°C until assayed radioimmunologically with commercial kits from Sorin (Italy). At 8:30 AM, before the test, subjects were informed about the procedure: They were told they would be given two harmless gas mixtures containing different percentages of CO2 and 02 and that they might experience sensations ranging from a few neurovegetative symptoms to a brief clear experience of anxiety, but the possibility of a panic attack was not mentioned. At 9:00 AM, subjects completed the State-Trait Anxiety Inventory for anxiety state (STAI-1) (Spielberger 1970) and vital capacity was measured. Subjects then inhaled one vital capacity of compressed air (placebo), and about 30 minutes later one vital capacity of 35% CO2-65% 02. At the end of each inhalation, subjects were asked to hold their breath for 4 seconds. The test was considered valid only if they had inhaled at least 80% of the previously measured vital capacity. Immediately before and after each inhalation, patients were invited to fill in a Visual Analogue Scale for anxiety (VAS-A), which describes the degree of global subjective anxiety on a continuum from 0 (no anxiety) to 100 (the worst anxiety ever imaginable) and a self-rated scale assessing the 13 DSM-III-R panic symptoms on a 5-point scale (0= absent, 1= mild, 2= moderate, 3-- severe, 4= very intense), obtaining a "Total Symptom Score" (TSS) which may be considered an index of the global symptomatological reaction to the inhalations. The same procedure was repeated on the second day of the challenge.
Provoked Panic A nacks According to Sanderson et al (1989), a provoked panic attack was defined as the following: a) presence of a sensation of fear or panic; b) at least four symptoms among those described in DSM-III-R, including c) at least one of the DSM-III-R cognitive symptoms (fear of dying, going crazy, or losing control).
Data Analysis Significances of differences for continuous variables, comparing patients and controls, were determined by Student's t-test, while significance of differences for dichotomous variables were determined by chi-square analysis. Pearson's correlation analysis was applied where appropriate. To assess the "order of phases" effect on A VAS-A
530
BIOLPSYCHIATRY 1995;37:528 532
G. Perna et al
(post-gas V A S - A minus pre-gas VAS-A) and A TSS (postgas TSS minus pre-gas TSS), preliminary two-way analysis of variance (ANOVA), in which diagnosis (D) and order of phases (O) were the grouping factors, was applied. To compare STAI-1, A V A S - A to 35% CO2, A TSS to 35% CO2, PRG, ESTR, PRL, FSH, LH, and ESTR/PROG ratio (EP), index of the balance between ESTR and PRG, between follicular and luteal phases in both patients and controls, multivariate A N O V A ( M A N O V A ) , in which phase (follicular vs. luteal) was treated as a repeated measures factor and diagnosis was the grouping factor, was applied. If any significant differences were found by MANOVAs, t-tests with Bonferroni' s correction applied post-hoe.
M A N O V A showed significant values for the diagnosis x procedure x gas (air vs. CO2) interaction, but as A V A S - A ( F = 7.49; d f = 1,13;p --< .02) and as A TSS ( F = 5.73; d f = 1,13; p = .03). Patients had significantly higher A V A S - A 43.6 --_ 26.8 vs. 22.5 --- 18.5) and A TSS (13.6 -+- 8.7 vs. 7.7 ± 3.3) after CO2 inhalation in the early follicular than in the midluteal phase, while controls had no significant reaction in either phase (Figure 1). Seven patients (70%) experienced provoked panic attacks after 35% CO2 inhalation in the follicular phase, but three of these did not panic in the luteal phase. Three patients (30%) and all controls did not panic in either phase. Compressed air was not able to induce any panic attack in either patients or controls.
Results
Discussion
Age and menstrual cycle length did not differ for patients and controls. M A N O V A showed significant phase (follicular vs. luteal)(P) effects for PRG ( F = 62.61 ; df = 1,15; p -< .001), ESTR ( F = 30.74; df = 1,15;p <- .001), ESTR/PRG ratio (EP)(F = 24.17; df = 1,15; p - .001), and FSH ( F = 22.63; df = 1,15; p -< .001), but not for LH and PRL. As expected, PRG, ESTR, and F S H were higher in the luteal than in the follicular phase, while EP was higher in the follicular phase, thus confirming that patients and controls had normal cyclic fluctuations of the sex hormones. Neither diagnosis (D) nor P×D interactions differed significantly with hormone levels (Tables 1 and 2). Progesterone levels determined in the luteal phase suggested that all the women tested ovulated. There was no significant correlation between hormone levels and reactivity to 35% CO2 in either phase. There was a significant diagnosis effect, but not a phase or PxD effect on the STAI-I score. Patients had higher STAI- 1 scores than controls. There was no significant "order of phases" effect on reactivity to 35% CO2.
The results clearly indicate stronger reactivity to 35% CO2 during the early follicular than during the midluteal phases of women with PD. The phenomenon was not seen in controis. The different reactivities between patients and controis could not be explained by hormone levels, which were normal in both groups. The different reactivities between phases in women with PD could not be explained by baseline anxiety, which was similar in the two phases of the menstrual cycle. The repeated administration of CO2 and its possible habituation effect cannot be invoked in the explanation, since no order of phases effect was found. Since PRG and ESTR are high and the EP ratio is low during the luteal phase, and the opposite is true in the follicular phase, the different reactivity might be related to different hormonal balance. It has been suggested that PRG has anxiolytic properties, acting through both potentiation of the adenosine function (Phillis 1986) and through barbiturate-like modulatory effects on the gamma-aminobutyric acid receptor complex (Majewska et al 1986; Wieland et al 1991). It has also been suggested that PRG influences CO2 chemosensitivity by
Table 2. Clinical and Hormonal Characteristics of Sample Controls (n=7)
Panic patients (n = 10)
STAI-I score Progesterone (ng/ml) Estradiol (pg/ml) Estr./Prog. Prolactin (ng/ml) FSH (UI/I) LH (UI/1)
Early-follicular phase
Midluteal phase
Early-follicular phase
Midluteal phase
49.6 _+ 15.5 0.5 + 0.7 41.7 + 13.7 247.9 ± 172.0 5.5 + 2.4 4.6 _+4.9 3.9 + 1.7
49.6 -+ 15.2 14.8 -+ 7.0 95.1 -+ 37.6 9.5 ± 9.4 7.8 ± 4.4 7.8 -+ 2.3 6.5 ± 8.9
31.7 ± 2.9 0.2 -+ 0.1 28.2 -+ 9.7 205.6 +- 120.0 6.9 + 3.5 3.0 ± 1.7 4.3 -+ 2.2
33.0 ± 5.0 15.8 -+ 8.5 82.6 -+ 38.3 32.3 -+ 72.7 6.6 -+ 2.4 6.7 ± 9.0 5.0 ± 2.3
Allvalues,exceptforagoraphobia,areexpressedas mean+ SD.
Menstrual Cycle-Related Sensitivity to CO: in Panic Patients
BIOLPSYCHIATRY
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1995;37:528-532
A VAS-A
Panic Patients
A VAS-A
100
100
80
8O
60
60
40
,o
20
2O
0
:
~
-20
0
-20 Early Follicular
M id Luteal
Controls
"~
Early Follicular
M id Luteal
A VAS-A: VAS-A post CO2 minus VAS-A pre CO2 Figure 1 Influence of menstrual cycle on subjective anxiety response to 35% C O 2 in panic patients and controls.
provoking an increase in minute ventilation and a decrease in pCO2 (Zwillich et al 1978; Klein 1993). According to Klein's (1993) hypothesis of the pathogenesis of PD, the widened gap between the "suffocation alarm threshold" and low pCO2 during the luteal phase might make panic attacks less likely. The increase in estrogen levels in the luteal phase may, instead, have an anxiogenic effect by increasing plasma noradrenaline (NA) levels, as reported for this period of the cycle, by inhibition of presynaptic NA reuptake, or by reduction of catecholamine degradation (B lure et al 1991), or all of these. Thus, the different reactivities to 35% CO2 during the menstrual cycle in women with PD might be explained by the modification of the balance between ESTR and PRG. Our findings, although limited by the small number of
subjects tested, strongly suggest that fluctuations of hormones in the menstrual cycle do influence reactivity to CO2, either primarily or less directly. Although sex does not influence the reactivity to 35% CO2 (Perna et al, 1994), these data plus the higher prevalence of PD in women, the influence of pregnancy and the infrequency of onset of PD in the prepubertal age or after menopause (Klein 1993), indicate a significant role of ovarian hormones in the clinical modulation of PD. If our data will be confirmed, investigators using biological challenge procedures might be careful in selecting, establishing, and describing the menstrual cycle phase during which women undergo the challenges, since apparent differences in responses to the experimental procedure may be related to this factor. It will be of interest to test women on contraceptives and in very early menopause.
References American Psychiatric Association ( 1987): DSM-II1-R: Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington DC: American Psychiatric Press. Breier A, Charney D, Heninger (1986): Agoraphobia with panic attacks: development, diagnostic stability, and course of illness. Arch Gen Psychiat~, 43:1029-1036. Blum I, Nessiel L, David A, et al ( 1992): Plasma neurotransmitter profile during different phases of the ovulatory cycle. J Clin Endocrinol Metabo175:924-929.
Brambilla F, Perna G, Garberi A, Nobile P, Bellodi L (in press): GH response to GH-RH and Clonidine stimulation in panic disorder. Psychoneuroendocrinology. Cameron OG, Kuttesch D, McPhee K, Curtis GC (1988): Menstrual fluctuation in the symptoms of panic anxiety. J Affective Disord 15:169-174.
Charney DS, Heninger GR (1986): Abnormal regulation of noradrenergic function in panic disorders. Arch Gen Psychiatry 43:1042-1054. Cohen M, White P ( 1951): Life situations, emotions, and neurocirculatory asthenia (anxiety neurosis, neurasthenia, effort syndrome). Psychosom Med 13:335-357. Cook BL, Noyes R, Garvey MJ, Beach V, Sobotka J, Chaudhry D (1990): Anxiety and the menstrual cycle in panic disorder. J Affective Disord 19:221-226. Cowley DS, Roy-Byrne PP (1989): Panic Disorder during pregnancy. J Psychosom Obstet Gynaecol 10:193-210. Deci PA, Lydiard RB, Santos AB, Arana GW (1992): Oral contraceptives and Panic Disorder. J Clin Psychiatry' 53:163-165. Dutton K, Blanksby BA, Morton AR (1989): CO2 sensitivity
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changes during the menstrual cycle. J Appl Physiol 67:517-522.
Price WA, Heil D (1988): Estrogen-induced panic attacks. Psychosomatics 29:433-435.
England SJ, Farhi LE (1976): Fluctuations in alveolar CO., and in base excess during the menstrual cycle. Respir Physiol 26:157-161.
Robins L, Helzer JE, Cottler L, Goldring E (1989): NIHM Diagnostic Interview Schedule: Version III-R (DIS-R). St Louis, MO: Washington University School of Medicine. Sandberg D, Fyer AJ, Endicott J (1986): Premenstrual Changes in Anxiety Patients. Presented at the Annual Meeting of the American Psychiatric Association. Sandberg D, Endicott J, Harrison W, Nee J, Gorman J (1993): Sodium lactate infusion in late luteal phase dysphoric disorder. Psychiatry Res 46:7%88. Sanderson WC, Rapee RM, Barlow DH (1989): The influence of an illusion of control on panic attacks induced via inhalation of 5.5% carbon dioxide-enriched air. Arch Gen Psychiat©' 46:157-162. Spielberger CD, Gorsuch R, Lushere R (1970): STA1 Manual for the State-Trait AnxieO; lnventoo,. Palo Alto, CA: Consulting Psychologists Press. Stein MB, Schmidt PJ, Rubinow DR, Uhde TW (1989): Panic disorder and the menstrual cycle: panic disorder patients, healthy control subjects, and patients with premenstrual syndrome. Arch Gen Psychiatr), 146:1299 1303. Ushiroyama T, Okamoto Y, Toyoda K, Sugimoto O (1992): A case of panic disorder induced by oral contraceptive. Acta Obstet Gynecol Seand 71:78-80.
Facchinetti F, Romano G, Fava M, Genazzani AR ( 1992): Lactate infusion induces panic attacks in patients with premenstrual syndrome. Psychosom Med 54:288-296. George DT, Ladenheim JA, Nutt DJ (1987): Effect of pregnancy on panic attacks. Am J Psychiatry 144:1078-1079. Gorman J, Liebowitz MR, Fyer AJ, Stein J ( 1989): A neuroanatomical hypothesis for panic disorder. A m J PsychiatO" 146:148-161. Gorman J, Papp LA, Martinez J, et al (1990): High dose carbon dioxide challenge test in anxiety disorders patients. Biol Psychiato' 28:743-757. Griez E, Lousberg H, Van den Hour MA, Van der Molen GM (1987): CO2 vulnerability in panic disorder. Psychiato' Res 20:87-95. Harrison WM, Sandberg D, Gorman JM, et al ( 1989): Provocation of panic with carbon dioxide inhalation in patients with premenstrual dysphoria. Psychiatry Res 27:183-192. Klein DF (1964): Delineation of two drug-responsive anxiety syndromes. Ps>'chopharmacologia 5:397-408. Klein DF (1993): False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen PsychiatO, 50:306-317, Marcus S, Buka S, McEvoy L, Zeena I, Robins L (1990): NIHM Diagnostic Interview Schedule." Data Ento' and Verification, Version 1.0 Program. St Louis, MO: Washington University. Majewska MD, Harrison NL, Schwarthz RD, Barker JL, Paul SM (1986): Steroid metabolites are barbiturate-like modulator of the GABA receptor. Science 232:1004-1007. Metz A, Sichel DA, GoffDC ( 1988): Postpartum panic disorder. J Clin Ps),chiatr)' 49:278-279. Metz A, Goff DC, Sichel DA ( 1989): Reply: postpartum disorder. J Clin Psychiatry 50:269. Pema G, Battaglia M, Garberi A, Arancio C, Bertani A. Bellodi L (1994): Carbon Dioxide/Oxygen challenge test in panic disorder. Psychiatry Res 52:158-171. Phillis J (1986): Potentiation of the depression by adenosine of rat cerebral, cortical neurones by progestational agents. BrJ Ph~trmaco189:693-702.
Verburg C, Griez E, Meijer J (in press): Increase of panic during second part of pregnancy. Eur Psychiatry. Villeponteaux VA, Lydiard RB, Laraia MT, Stuart GW, Ballenger JC ( 1992): The effects of pregnancy on preexisting panic disorder. J Clin Psychiatry 53:201-203. Wieland S, Lan NC, Miradeseghi S, Gee KW (1991): Anxiolytic activity of the progesterone metabolite 5 alfa-pregnan-3 alfaol-20-one. Brain Res 565:263-268. Wheeler EO, White PD, Reed EW, et al (1950): Neurocirculatory asthenia (anxiety neurosis, effort syndrome, neurasthenia): a twenty-year follow up study of 173 patients. JAMA 142:878890. Zwillich CW, Natalino MR, Sutton FD, Weil JV ( 1978): Effects of progesterone on chemosensitivity in normal men. J Lab Clin Med 92: 262-269.
In a double blind, random, cross-over design, 10 patients and seven controls inhaled one vital capacity of 35% C02-65% Oz during their early-follicular and midluteal phases. Anxiety after CO: intake was significantly stronger in the early-follicular phase than in the midluteal phase for patients. Controls had no anxie~, reactions. Key Words: Sex hormones, panic, CO2
Introduction Clinical evidence and data from controlled studies suggest that sex hormones might modulate the clinical expression of panic disorder (PD) (Klein 1993). Clinical observations and data from retrospective studies (Breier et al 1986; Sandberg et al 1986) suggest that PD is exacerbated in the premenstrual period, perhaps related to the rapid fall of blood progesterone (Klein 1993), whereas data from prospective studies are inconsistent. Cameron et al (1988) found a premenstrual exacerbation of the severity of panic attacks, while Stein et al (1989) and Cook et al (1990) did not find any significant relationship between menstrual cycle and severity or frequency of panic. It has been suggested that pregnancy influences the clinical expression of PD. Two early retrospective studies by Cohen and White (1951 ) and Wheeler et al (1950) reported an exacerbation of panic symptomatology, while a case
From the Anxiety Disorders Clinical and Research Unit. Department of Neuropsy chiatric Sciences, University of Milan San Raffaele Hospital (GP, CA. LB), and Centro di Psiconeuroendocrinologia, Psychiatric Hospital Paolo Pini (FB), Milan, Italy. Address reprint requests to Prof. L. Bellodi, Dept. of Neuropsychiatric Sciences, University of Milan, San Raffaele Hospital. 29 via Prinetti, 20127, Milan, Italy. Received January 31.1994; revised May 1994.
© 1995 Society of Biological Psychiatry
study by George et al (1987) and retrospective studies by Klein (1964), Cowley and Roy-Byrne (1989), and Villeponteaux et al (1992) reported improvement of PD during pregnancy. Finally, a case study by Verburg et al (in press) reported improvement of PD in the first half of pregnancy and a recurrence of panic symptoms in the second half. Panic symptomatology has been reported to worsen postpartum (Metz et al 1988, 1989), with lactation apparently being protective (Klein 1993; Cowley and Roy-Byrne 1989). Oral contraceptives (Deci et al 1992; Ushiroyama et al 1992) and estrogen replacement treatment (Price et al 1988) have been reported to provoke panic attacks. Finally, late luteal phase dysphoric disorder has shown rates of provoked panic-like attacks similar to those in PD (Harrison et al 1989; Facchinetti et al 1992; Sandberg et a11993). Hypersensitivity to CO2 (Gorman et al 1989), in the context of the "False Suffocation Alarms" theory developed by Klein (1993), and abnormal noradrenergic function (Charney et al 1986; Brambilla et al, in press) may be etiopathogenetic factors in PD. Both fluctuate during the menstrual cycle, possibly influenced by progesterone (England and Farhi 1976; Dutton et al 1989) and estrogen levels (Blum et al 1992). We have investigated the changes in anxiety provoked in PD patients by inhalation of one vital capacity of 35% CO2 (Griez et al 1987; Perna et al 1994) during the early follicular and midluteal phases. 0006-3223/95/$09.50 SSDI 0006-3223(94)00154-U
Menstrual Cycle-Related Sensitivity to CO2 in Panic Patients
T a b l e 1. D e m o g r a p h i c C h a r a c t e r i s t i c s o f S a m p l e
Age (years) Menstrual cycle length (days) Age at onset (years) No. of panic attacks during last month Agoraphobia
Panic patients (n = 10)
Controls (n = 7)
32.t + 6.6 27.1 ~+ 1.8 29.1 ~ 6.7
25.9 --+ 5.4 28,6 + 1.8
5.6 _+ 4.4 8
All values, except for agoraphobia, are expressed as mean + SD.
Methods Subjects The subjects were 10 physically healthy women with PD, consecutively recruited over I year at the Anxiety Disorders Clinical and Research Unit, San Raffaele Hospital, Milan, and seven healthy women without any lifetime Axis I disorders and with no personal histories of panic attacks. Diagnoses were made according to the Diagnostic Interview Schedule, Revised (DIS-R) (Robins et al 1989), and the data collected were analyzed by computer software (Marcus et al 1990). None of the subjects participating to the study met DSM-III-R (APA 1987) criteria for Late Luteal Phase Dysphoric Disorder. Table 1 lists the demographic and clinical characteristics of the sample. Criteria for exclusion were: current or recent (past 6 months) pregnancy, lactation, or abortion; irregular menstrual cycle; endocrinopathies; use of oral contraceptives; chronic use of any medication, and, for patients, any lifetime psychiatric diagnoses other than PD according to DSM-III-R (APA 1987). Participants gave their informed consent and were requested to avoid medications affecting sex hormone or prolactin (PRL) levels and any psychotropic drug for at least 2 weeks, alcohol for at least 36 hours, xanthines, smoking, and food for at least 8 hours before testing.
Procedure The investigators who performed the challenges were blind to the menstrual phase and the diagnosis of the participants. Participants in the study were blind to the order of administration of gas mixtures. According to period of admission to the study, the first day of the challenge in 5 patients and 3 controls coincided with the midluteal phase, and in 5 patients and 4 controls with the early follicular phase. Order of gas administration was not randomized, since previous studies showed no significant effect of order on reactivity to 35% CO2 (Gorman et al 1990; Perna et al, 1994). 35% CO2 challenges were given in the very early follicular phase (day 4 of the cycle), in which pituitary and ovarian hormone levels are still minimal, and in the midluteal phase, (day -8
B1OL PSYCHIATRY ! 995:37:528-532
529
before menses) in which most of the hormonal levels are maximal. Days 4 and - 8 were based on regular menstrual cycles. On the first day of the challenge, at 8:00 AM blood was drawn and treated with ethylenediamine tetraacetic acid (EDTA), and assays were drawn for progesterone (PRG), estrogen (ESTR), follicle-stimulating hormone (FSH), and luteotrophic hormone (LH), prolactin (PRL). Plasma was frozen at -20°C until assayed radioimmunologically with commercial kits from Sorin (Italy). At 8:30 AM, before the test, subjects were informed about the procedure: They were told they would be given two harmless gas mixtures containing different percentages of CO2 and 02 and that they might experience sensations ranging from a few neurovegetative symptoms to a brief clear experience of anxiety, but the possibility of a panic attack was not mentioned. At 9:00 AM, subjects completed the State-Trait Anxiety Inventory for anxiety state (STAI-1) (Spielberger 1970) and vital capacity was measured. Subjects then inhaled one vital capacity of compressed air (placebo), and about 30 minutes later one vital capacity of 35% CO2-65% 02. At the end of each inhalation, subjects were asked to hold their breath for 4 seconds. The test was considered valid only if they had inhaled at least 80% of the previously measured vital capacity. Immediately before and after each inhalation, patients were invited to fill in a Visual Analogue Scale for anxiety (VAS-A), which describes the degree of global subjective anxiety on a continuum from 0 (no anxiety) to 100 (the worst anxiety ever imaginable) and a self-rated scale assessing the 13 DSM-III-R panic symptoms on a 5-point scale (0= absent, 1= mild, 2= moderate, 3-- severe, 4= very intense), obtaining a "Total Symptom Score" (TSS) which may be considered an index of the global symptomatological reaction to the inhalations. The same procedure was repeated on the second day of the challenge.
Provoked Panic A nacks According to Sanderson et al (1989), a provoked panic attack was defined as the following: a) presence of a sensation of fear or panic; b) at least four symptoms among those described in DSM-III-R, including c) at least one of the DSM-III-R cognitive symptoms (fear of dying, going crazy, or losing control).
Data Analysis Significances of differences for continuous variables, comparing patients and controls, were determined by Student's t-test, while significance of differences for dichotomous variables were determined by chi-square analysis. Pearson's correlation analysis was applied where appropriate. To assess the "order of phases" effect on A VAS-A
530
BIOLPSYCHIATRY 1995;37:528 532
G. Perna et al
(post-gas V A S - A minus pre-gas VAS-A) and A TSS (postgas TSS minus pre-gas TSS), preliminary two-way analysis of variance (ANOVA), in which diagnosis (D) and order of phases (O) were the grouping factors, was applied. To compare STAI-1, A V A S - A to 35% CO2, A TSS to 35% CO2, PRG, ESTR, PRL, FSH, LH, and ESTR/PROG ratio (EP), index of the balance between ESTR and PRG, between follicular and luteal phases in both patients and controls, multivariate A N O V A ( M A N O V A ) , in which phase (follicular vs. luteal) was treated as a repeated measures factor and diagnosis was the grouping factor, was applied. If any significant differences were found by MANOVAs, t-tests with Bonferroni' s correction applied post-hoe.
M A N O V A showed significant values for the diagnosis x procedure x gas (air vs. CO2) interaction, but as A V A S - A ( F = 7.49; d f = 1,13;p --< .02) and as A TSS ( F = 5.73; d f = 1,13; p = .03). Patients had significantly higher A V A S - A 43.6 --_ 26.8 vs. 22.5 --- 18.5) and A TSS (13.6 -+- 8.7 vs. 7.7 ± 3.3) after CO2 inhalation in the early follicular than in the midluteal phase, while controls had no significant reaction in either phase (Figure 1). Seven patients (70%) experienced provoked panic attacks after 35% CO2 inhalation in the follicular phase, but three of these did not panic in the luteal phase. Three patients (30%) and all controls did not panic in either phase. Compressed air was not able to induce any panic attack in either patients or controls.
Results
Discussion
Age and menstrual cycle length did not differ for patients and controls. M A N O V A showed significant phase (follicular vs. luteal)(P) effects for PRG ( F = 62.61 ; df = 1,15; p -< .001), ESTR ( F = 30.74; df = 1,15;p <- .001), ESTR/PRG ratio (EP)(F = 24.17; df = 1,15; p - .001), and FSH ( F = 22.63; df = 1,15; p -< .001), but not for LH and PRL. As expected, PRG, ESTR, and F S H were higher in the luteal than in the follicular phase, while EP was higher in the follicular phase, thus confirming that patients and controls had normal cyclic fluctuations of the sex hormones. Neither diagnosis (D) nor P×D interactions differed significantly with hormone levels (Tables 1 and 2). Progesterone levels determined in the luteal phase suggested that all the women tested ovulated. There was no significant correlation between hormone levels and reactivity to 35% CO2 in either phase. There was a significant diagnosis effect, but not a phase or PxD effect on the STAI-I score. Patients had higher STAI- 1 scores than controls. There was no significant "order of phases" effect on reactivity to 35% CO2.
The results clearly indicate stronger reactivity to 35% CO2 during the early follicular than during the midluteal phases of women with PD. The phenomenon was not seen in controis. The different reactivities between patients and controis could not be explained by hormone levels, which were normal in both groups. The different reactivities between phases in women with PD could not be explained by baseline anxiety, which was similar in the two phases of the menstrual cycle. The repeated administration of CO2 and its possible habituation effect cannot be invoked in the explanation, since no order of phases effect was found. Since PRG and ESTR are high and the EP ratio is low during the luteal phase, and the opposite is true in the follicular phase, the different reactivity might be related to different hormonal balance. It has been suggested that PRG has anxiolytic properties, acting through both potentiation of the adenosine function (Phillis 1986) and through barbiturate-like modulatory effects on the gamma-aminobutyric acid receptor complex (Majewska et al 1986; Wieland et al 1991). It has also been suggested that PRG influences CO2 chemosensitivity by
Table 2. Clinical and Hormonal Characteristics of Sample Controls (n=7)
Panic patients (n = 10)
STAI-I score Progesterone (ng/ml) Estradiol (pg/ml) Estr./Prog. Prolactin (ng/ml) FSH (UI/I) LH (UI/1)
Early-follicular phase
Midluteal phase
Early-follicular phase
Midluteal phase
49.6 _+ 15.5 0.5 + 0.7 41.7 + 13.7 247.9 ± 172.0 5.5 + 2.4 4.6 _+4.9 3.9 + 1.7
49.6 -+ 15.2 14.8 -+ 7.0 95.1 -+ 37.6 9.5 ± 9.4 7.8 ± 4.4 7.8 -+ 2.3 6.5 ± 8.9
31.7 ± 2.9 0.2 -+ 0.1 28.2 -+ 9.7 205.6 +- 120.0 6.9 + 3.5 3.0 ± 1.7 4.3 -+ 2.2
33.0 ± 5.0 15.8 -+ 8.5 82.6 -+ 38.3 32.3 -+ 72.7 6.6 -+ 2.4 6.7 ± 9.0 5.0 ± 2.3
Allvalues,exceptforagoraphobia,areexpressedas mean+ SD.
Menstrual Cycle-Related Sensitivity to CO: in Panic Patients
BIOLPSYCHIATRY
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1995;37:528-532
A VAS-A
Panic Patients
A VAS-A
100
100
80
8O
60
60
40
,o
20
2O
0
:
~
-20
0
-20 Early Follicular
M id Luteal
Controls
"~
Early Follicular
M id Luteal
A VAS-A: VAS-A post CO2 minus VAS-A pre CO2 Figure 1 Influence of menstrual cycle on subjective anxiety response to 35% C O 2 in panic patients and controls.
provoking an increase in minute ventilation and a decrease in pCO2 (Zwillich et al 1978; Klein 1993). According to Klein's (1993) hypothesis of the pathogenesis of PD, the widened gap between the "suffocation alarm threshold" and low pCO2 during the luteal phase might make panic attacks less likely. The increase in estrogen levels in the luteal phase may, instead, have an anxiogenic effect by increasing plasma noradrenaline (NA) levels, as reported for this period of the cycle, by inhibition of presynaptic NA reuptake, or by reduction of catecholamine degradation (B lure et al 1991), or all of these. Thus, the different reactivities to 35% CO2 during the menstrual cycle in women with PD might be explained by the modification of the balance between ESTR and PRG. Our findings, although limited by the small number of
subjects tested, strongly suggest that fluctuations of hormones in the menstrual cycle do influence reactivity to CO2, either primarily or less directly. Although sex does not influence the reactivity to 35% CO2 (Perna et al, 1994), these data plus the higher prevalence of PD in women, the influence of pregnancy and the infrequency of onset of PD in the prepubertal age or after menopause (Klein 1993), indicate a significant role of ovarian hormones in the clinical modulation of PD. If our data will be confirmed, investigators using biological challenge procedures might be careful in selecting, establishing, and describing the menstrual cycle phase during which women undergo the challenges, since apparent differences in responses to the experimental procedure may be related to this factor. It will be of interest to test women on contraceptives and in very early menopause.
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